Medical devices having a coating of inorganic material

ABSTRACT

In one aspect, a medical device has a first configuration and a second configuration, a reservoir containing a therapeutic agent, and a barrier layer disposed over the reservoir, wherein the barrier layer comprises an inorganic material. In another aspect, a medical device has a reservoir containing a therapeutic agent, a barrier layer disposed over the reservoir, wherein the barrier layer comprises an inorganic material, and a swellable material disposed between the barrier layer and a surface of the medical device, wherein the swellable material is a material that swells upon exposure to an aqueous environment. In yet another aspect, a medical device has a multi-layered coating having alternating reservoir layers and barrier layers, and a plurality of excavated regions penetrating through at least a partial thickness of the multi-layered coating. In yet another aspect, a medical device has a polymer layer comprising a block co-polymer, wherein the polymer layer contains a therapeutic agent, and a barrier layer disposed over the polymer layer, wherein the barrier layer comprises an inorganic material, and wherein the barrier layer has a plurality of discontinuities. Methods of forming coatings on medical devices and methods of delivering therapeutic agents to body sites are also disclosed.

CROSS REFERENCE TO RELATED APPLICATION

The present application claims priority to U.S. provisional applicationSer. No. 61/047,002 filed Apr. 22, 2008, the disclosure of which isincorporated herein by reference in its entirety.

TECHNICAL FIELD

The present invention relates to medical devices, and in particular,medical devices having a coating containing a therapeutic agent.

BACKGROUND

Many implantable medical devices are coated with drugs that are elutedfrom the medical device upon implantation. For example, some vascularstents are coated with a drug which is eluted from the stent fortreatment of the vessel and/or to prevent some of the unwanted effectsand complications of implanting the stent. In such drug-eluting medicaldevices, various methods have been proposed to provide a mechanism fordrug elution. However, there is a continuing desire for improved devicesand methods for providing drug elution from medical devices.

SUMMARY

In one aspect, the present invention provides a medical device having afirst configuration (e.g., unexpanded) and a second configuration (e.g.,expanded), wherein the medical device comprises: (a) a reservoircontaining a therapeutic agent; and (b) a barrier layer disposed overthe reservoir, wherein the barrier layer comprises an inorganicmaterial, wherein the barrier layer has a first permeability to thetherapeutic agent when the medical device is in the first configurationand a second permeability to the therapeutic agent when the medicaldevice is in the second configuration, and wherein the secondpermeability is greater than the first permeability.

In another aspect, the present invention provides a medical devicecomprising: (a) a reservoir containing a therapeutic agent; (b) abarrier layer disposed over the reservoir, wherein the barrier layercomprises an inorganic material; and (c) a swellable material disposedbetween the barrier layer and a surface of the medical device, whereinthe swellable material is a material that swells upon exposure to anaqueous environment.

In yet another aspect, the present invention provides a medical devicehaving a multi-layered coating, wherein the multi-layered coatingcomprises: (a) a first reservoir layer over a surface of the medicaldevice, wherein the first reservoir layer comprises a first therapeuticagent; (b) a first barrier layer over the first reservoir layer, whereinthe first barrier layer comprises a first inorganic material; (c) asecond reservoir layer over the first barrier layer, wherein the secondreservoir layer comprises a second therapeutic agent; (d) a secondbarrier layer over the second reservoir layer, wherein the secondbarrier layer comprises a second inorganic material; and (e) a pluralityof excavated regions penetrating through at least a partial thickness ofthe multi-layered coating.

In yet another aspect, the present invention provides a medical devicecomprising: (a) a polymer layer comprising a block co-polymer, whereinthe polymer layer contains a therapeutic agent; and (b) a barrier layerdisposed over the polymer layer, wherein the barrier layer comprises aninorganic material, and wherein the barrier layer has a plurality ofdiscontinuities.

The present invention also provides methods for forming a coating onmedical devices and methods for delivering a therapeutic agent to a bodysite.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1D show various views of a stent according to an embodiment ofthe present invention. FIG. 1A shows a top view of a strut on the stent.FIG. 1B shows a cross-section perspective view of a portion of the stentstrut in FIG. 1A. FIG. 1C shows a cross-section side view of the stentstrut in FIG. 1B, before the stent is expanded. FIG. 1D shows across-section side view of the stent strut in FIG. 1B, after the stentis expanded.

FIGS. 2A-2C show cross-section views of a strut on a stent according toanother embodiment. FIG. 2A shows the stent strut before the stent isexpanded. FIG. 2B shows the stent strut after the stent is expanded.FIG. 2C shows the stent strut after degradation of the plugs.

FIGS. 3A and 3B show cross-section views of a strut on a stent accordingto yet another embodiment. FIG. 3A shows the stent strut before thestent is expanded. FIG. 3B shows the stent strut after the stent isexpanded.

FIGS. 4A and 4B show cross-section views of a strut on a stent accordingto yet another embodiment. FIG. 4A shows the stent strut before thestent is expanded. FIG. 4B shows the stent strut after the stent isexpanded.

FIGS. 5A and 5B show cross-section views of a strut on a stent accordingto yet another embodiment. FIG. 5A shows the stent strut before thestent is expanded. FIG. 5B shows the stent strut after the stent isexpanded.

FIGS. 6A and 6B show cross-section views of a strut on a stent accordingto yet another embodiment. FIG. 6A shows the stent strut before thestent is expanded. FIG. 6B shows the stent strut after the stent isexpanded.

FIGS. 7A and 7B show cross-section views of a strut on a stent accordingto yet another embodiment. FIG. 7A shows the stent strut before thewater-swellable layer is hydrated. FIG. 7B shows the stent strut afterthe water-swellable layer is hydrated.

FIGS. 8A and 8B show cross-section views of a strut on a stent accordingto yet another embodiment. FIG. 8A shows the stent strut before thehydrogel capsules are hydrated. FIG. 8B shows the stent strut after thehydrogel capsules are hydrated.

FIG. 9 shows a cross-section view of a strut on a stent having amulti-layered coating according to yet another embodiment.

FIG. 10 shows a cross-section view of a strut on a stent having amulti-layered coating according to yet another embodiment.

FIG. 11 shows a magnified view of the surface of a sputter-depositedlayer of gold.

FIG. 12 shows an atomic force microscopic image of the surface of anSIBS block polymer film.

FIG. 13 shows an example of a surface having feature elements (grooves)and feature domains (area enclosed by the grooves).

FIGS. 14A and 14B show cross-section views of a strut on a stentaccording to yet another embodiment. FIG. 14A shows the stent strutbefore dissolution of the polymer layer. FIG. 14B shows the stent strutafter dissolution of the polymer layer.

FIG. 15 shows a magnified view of the surface of a layer ofsputter-deposited gold with drug particles underneath.

FIG. 16 shows a magnified view of the surface of the gold layer of FIG.15, after additional sputter-deposition of gold onto the layer.

DETAILED DESCRIPTION

In one aspect, the present invention provides a medical device having afirst configuration and a second configuration. The medical devicecomprises a reservoir containing a therapeutic agent. A barrier layer isdisposed over the reservoir, wherein the barrier layer comprises aninorganic material.

Medical devices may have various types of first and secondconfigurations. In some cases, the medical device is an expandablemedical device having an unexpanded (first) configuration and anexpanded (second) configuration. For example, the medical device may bean expandable stent or vascular graft which is delivered to the targetbody site in an unexpanded configuration and then expanded to theexpanded configuration for implantation at the target site. Variousother types of first/second configurations are also possible, includingfor example, unbent/bent configurations, unstretched/stretchedconfigurations, or undeformed/deformed configurations.

The reservoir containing the therapeutic agent may be provided invarious ways. The reservoir may be the therapeutic agent formulationalone, or may comprise any structure that retains or holds thetherapeutic agent. For example, the reservoir may be a polymer layer orother layer over the medical device with the therapeutic agent disposedtherein. In another example, the reservoir may be created in the surfaceof the medical device (e.g., a porous surface), or the medical devicemay have pits, pores, cavities, or holes that contain the therapeuticagent.

The barrier layer comprises an inorganic material, which may be selectedon the basis of various considerations depending upon the particularapplication. For example, the inorganic material may be selected for itsbiologic properties (e.g., biocompatibility), structural properties(e.g., porosity), chemical properties (e.g., chemical reactivity),handling properties (e.g., storage stability), or the depositiontechniques that can be used. Suitable inorganic materials for use in thebarrier layer include inorganic elements, such as pure metals includingaluminum, chromium, gold, hafnium, iridium, niobium, palladium,platinum, tantalum, titanium, tungsten, zirconium, and alloys of thesemetals (e.g., nitinol); and inorganic compounds, such as metal oxides(e.g., iridium oxide or titanium oxide), metal nitrides, and metalcarbides, as well as inorganic silicides. Other suitable inorganicmaterials include certain carbon-containing materials that aretraditionally considered inorganic materials, such as carbonizedmaterials, carbon nanostructure materials, (e.g., carbon nanotubes,fullerenes, etc.), and diamond-like materials.

By being comprised of an inorganic material, the barrier layer may beuseful in improving the biocompatibility or therapeutic effectiveness ofthe medical device. For example, the barrier layer may be useful inprotecting body tissue from direct exposure to an underlying polymerlayer that is less biocompatible than the barrier layer. Also, thebarrier layer may present a more attractive surface for body tissue. Forexample, in the case of a vascular stent, the barrier layer may presenta surface that promotes the migration and growth of endothelial cells,which can help to reduce the incidence of adverse effects related tostent implantation.

In some cases, the barrier layer may be formed using any of variouslayer deposition processes. For example, layer deposition processes thatmay be suitable for forming the barrier layer include: chemical vapordeposition, plasma vapor deposition, sputtering, pulsed laserdeposition, sol-gel, evaporation (thermal, electron beam, etc.),molecular beam epitaxy, solution process (e.g., spray coating, dipcoating, roll coating, etc.), or electrodeposition (e.g.,electroplating, electrospray, etc.). The barrier layer may also beformed by carbonization (e.g., by laser heating or ion bombardment) of aprecursor carbon material (e.g., a polymer) to form a barrier layerformed of an inorganic carbonized material.

The process used to form the barrier layer can be selected on the basisof various considerations, such as the type of medical device, thevulnerability of the therapeutic agent to heat degradation, or the typeof inorganic material being used in the barrier layer. The thickness ofthe barrier layer will vary, depending upon the particular application.In some cases, the thickness of the barrier layer is in the range of 20nm to 10 μm, but other thicknesses are also possible.

The barrier layer has a first permeability to the therapeutic agent whenthe medical device is in the first configuration and a secondpermeability to the therapeutic agent when the medical device is in thesecond configuration, with the second permeability being greater thanthe first permeability. Various possible degrees of permeability arepossible for the first and second permeabilities of the barrier layer.In some cases, the first permeability does not provide a therapeuticallyeffective release profile of the therapeutic agent (e.g., negligible orzero permeability), whereas the second permeability does provide atherapeutically effective release profile of the therapeutic agent. Insome cases, the second permeability is at least 1.5-fold greater; and insome cases, at least 3.0-fold greater than the first permeability (wherethe first permeability is non-zero).

The second permeability is provided by discontinuities that are formedin the barrier layer when the medical device changes from the firstconfiguration (e.g., unexpanded) to the second configuration (e.g.,expanded). As used herein, the term “discontinuities” refers to discretedefects in the barrier layer that allow the passage of therapeuticagents through the barrier layer. Examples of such discrete defectsinclude fractures lines, cracks, breaks, gaps, faults, holes,perforations, and other openings through the full thickness of thebarrier layer. These discontinuities may have various dimensions andgeometries, which can affect the permeability of the barrier layer. Forexample, wider discontinuities can increase the permeability of thebarrier layer, and thus, increase the rate at which the therapeuticagent diffuses through the barrier layer. The discontinuities may belinear or curved, jagged or smooth, irregular or regular, or have any ofvarious other patterns.

In addition to providing the second permeability, the discontinuitiesmay also serve to relieve any stress on the adhesive bond between thebarrier layer and the underlying substrate when the medical deviceundergoes deformation. By allowing the formation of discontinuities inthe barrier layer, the barrier layer is made less sensitive to strain,thus relieving stress on the adhesive bond when the medical deviceundergoes deformation.

In certain embodiments, the medical device is provided in the firstconfiguration (e.g., unexpanded) with the barrier layer having aplurality of regions of structural weakness. As used herein, “regions ofstructural weakness” refers to regions of relative weakness in thebarrier layer such that when the barrier layer is strained,discontinuities will form and/or propagate in the regions of structuralweakness. In certain embodiments, the regions of structural weakness areexcavated regions in the barrier layer. As used herein, “excavatedregions” refers to voids (e.g., holes, slots, grooves, channels,etchings, scribe lines, perforations, pits, etc.) that are created byremoval of material using techniques that control the size, shape, andlocation of the voids. For example, such techniques include direct-writeetching using energetic beams (e.g., laser, ion, or electron),micromachining, microdrilling, or lithographic processes.

The excavated regions may have various geometries and dimensions, whichmay be adjusted to achieve the desired amount of weakness in thatparticular region of the barrier layer. The excavated regions may extendpartially or completely through the barrier layer. Increasing the depthof penetration of the excavated regions can increase the amount ofweakness in that particular region of the barrier layer. In some cases,the excavated regions have an average penetration depth of 10%-90%through the thickness of the layer, but other average penetration depthsare also possible. In some cases, the average penetration depth of theexcavated regions is greater than 10% of the thickness of the barrierlayer; and in some cases, greater than 33%; and in some cases, greaterthan 50%. Increasing the width of the excavated regions can alsoincrease the amount of weakness in the barrier layer in that particularregion. In some cases, the excavated regions have an average width inthe range of 10 nm to 1 μm, but other average widths are also possible.The overall ratio between the surface area of the excavated regions andthe non-excavated regions will vary depending upon the particularapplication. In some cases, the excavated regions may constitute 5-90%;and in some cases, 30-70% of the overall surface area, but other ratiosare also possible Also, the surface area ratio of the excavated regionsto the non-excavated regions may be different at different portions ofthe medical device.

For example, referring to the embodiment shown in FIGS. 1A-1D, a strut20 of an expandable stent 10 is coated with a polymer layer 30containing a therapeutic agent. Polymer layer 30 is coated with abarrier layer 40 formed of iridium oxide. Referring to FIG. 1A, showinga top view of a portion of stent strut 20, barrier layer 40 over stentstrut 20 has multiple scribe lines 42 that are formed by laser etching.FIG. 1B is a cross-section perspective view and FIG. 1C is across-section side view of portion 16 in FIG. 1A, showing barrier layer40, polymer layer 30, and stent strut 20 when stent 10 is in anunexpanded configuration. In this particular embodiment, scribe lines 42penetrate partially through barrier layer 40.

In operation, stent 10 is delivered to a body site in an unexpandedconfiguration. Once at the target body site, stent 10 is expanded. Asshown in FIG. 1D, upon expansion, deformation of the stent strutsimposes strain on barrier layer 40, causing the formation of cracks 44in barrier layer 40 along scribe lines 42. These cracks 44 allow thepassage of therapeutic agent from polymer layer 30 through barrier layer40 to the external environment.

The laser used in the etching process may be any of various laserscapable of ablating inorganic material, including excimer lasers.Various parameters, including for example, the wavelength, pulse energy,and/or pulse frequency of the laser, may be adjusted to achieve thedesired result. The laser can be applied using direct-write techniquesor by using masking techniques (e.g., laser lithography). In some cases,a cold ablation technique is used (e.g., using a femtosecond laser or ashort wavelength excimer laser), which may be useful in reducing anydamage to the therapeutic agent or, where a polymeric material is usedin the medical device, in reducing damage to the polymeric material.

In certain embodiments, the excavated regions may extend through thefull thickness of the barrier layer, with the excavated regions beingfilled with a biodegradable filler material. For example, referring tothe embodiment shown in FIGS. 2A and 2B, a stent strut 20 of anexpandable stent is coated with a polymer layer 30 containing atherapeutic agent. Polymer layer 30 is coated with a barrier layer 50,which has multiple perforations 52. Perforations 52 are filled withplugs 54, which comprises a biodegradable filler material, such as abiodegradable polymer, pharmaceutically acceptable salt or sugar, or abiodegradable metal (e.g., magnesium).

In operation, the stent is delivered to a body site in an unexpandedstate. Once at the target body site, the stent is expanded. As shown inFIG. 2B, upon expansion, deformation of the stent struts imposes strainupon barrier layer 50. This causes plugs 54 to partially detach orfracture, increasing the exposure of plugs 54 to the physiologic fluid.As shown in FIG. 2C, plugs 54 then undergo biodegradation such thatperforations 52 are made patent. This allows the passage of therapeuticagent from polymer layer 30 through perforations 52 to the externalenvironment.

In certain embodiments, the regions of structural weakness are regionswhere the barrier layer has reduced thickness relative to the fullthickness of the barrier layer. The regions of reduced thickness may becreated in various ways during the formation of the barrier layer. Inone example, the regions of reduced thickness may be created bydisposing the barrier layer on a textured surface such that the barrierlayer has reduced thickness in the regions that are located over theprotruding features of the textured surface. The protruding features maybe bumps, ridges, ribs, folds, corrugations, projections, prominences,elevations, or other features that protrude from the textured surface.The textured surface may form a pattern that is regular or irregular.

For example, referring to the embodiment shown in FIGS. 3A and 3B, astent strut 20 of an expandable stent is coated with a polymer layer 32.The surface of polymer layer 32 has a plurality of ridges 34. Polymerlayer 32 is coated with a barrier layer 60. The portions of barrierlayer 60 overlying ridges 34 are thinner portions 62 that have reducedthickness compared to the full thickness barrier layer 60.

In operation, the expandable stent is delivered to a body site in anunexpanded state. Once at the target body site, the expandable stent isexpanded. As shown in FIG. 3B, when the expandable stent is expanded,deformation of the stent struts imposes strain on barrier layer 60,causing the formation of cracks 64 in the thinner portions 62 of barrierlayer 60. These cracks 64 allow the passage of therapeutic agent frompolymer layer 30 through barrier layer 62 to the external environment.

The regions of structural weakness may be distributed in various ways ondifferent portions of the medical device. In certain embodiments, theregions of structural weakness are distributed uniformly throughout themedical device. In certain embodiments, the regions of structuralweakness in the barrier layer at one portion of the medical device hasdifferent characteristics than those at a different portion of themedical device. In some cases, the regions of structural weakness arearranged and/or constructed to accommodate the location-dependentvariation in strain forces that the barrier layer will experience whenthe medical device is changed from the first configuration to the secondconfiguration. For example, in the expandable stent 10 of FIG. 1A,different portions of stent strut 20 will undergo varying amounts ofdeformation when stent 10 is expanded. In this particular stent, portion12 of stent strut 20 will undergo more deformation than portion 14,causing more strain in barrier layer 40 over portion 12 than overportion 14. As such, the regions of structural weakness can be madeweaker in areas where barrier layer 40 undergoes less strain in order toachieve the desired amount of second permeability in those areas ofbarrier layer 40.

For example, referring to the embodiment shown in FIGS. 4A and 4B, astent strut 20 of an expandable stent is coated with a polymer layer 30containing a therapeutic agent. Polymer layer 30 is coated with abarrier layer 70. Referring to FIG. 4A, in portions of the stent wherethe stent struts experience greater deformation during expansion,barrier layer 70 has shallow scribe lines 72. Referring to FIG. 4B, inportions of the stent where the stent struts experience less deformationduring expansion, barrier layer 70 has deep scribe lines 74. In anotherexample, referring to the embodiment shown in FIGS. 5A and 5B, a stentstrut 20 of an expandable stent is coated with a polymer layer 30containing a therapeutic agent. Polymer layer 30 is coated with abarrier layer 80. The shape of the base of the scribe lines can alsohave an effect on crack propagation, with blunt or larger radius tipssustaining less stress concentration than sharp or smaller radius tips.Thus, referring to FIG. 5A, in portions of the stent where the stentstruts experience less deformation during expansion, barrier layer 80has narrow scribe lines 82. Referring to FIG. 5B, in portions of thestent where the stent struts experience greater deformation duringexpansion, barrier layer 80 has wide scribe lines 84. In yet anotherexample, referring to the embodiment shown in FIGS. 6A and 6B, a stentstrut 20 of an expandable stent is coated with a polymer layer 30containing a therapeutic agent. Polymer layer 30 is coated with abarrier layer 90. Referring to FIG. 6A, in portions of the stent wherethe stent struts experience greater deformation during expansion,barrier layer 90 has a lower density of scribe lines 92. Referring toFIG. 6B, in portions of the stent where the stent struts experience lessdeformation during expansion, barrier layer 90 has a higher density ofscribe lines 92.

In another aspect, the present invention provides a medical devicehaving a reservoir containing a therapeutic agent. Further, a barrierlayer is disposed over the reservoir, wherein the barrier layercomprises an inorganic material. Further, a swellable material isdisposed between the barrier layer and a surface of the medical device,wherein the swellable material is a material which swells upon exposureto an aqueous environment. Such swellable materials includewater-swellable polymers and oxidizable metals. The composition andstructure of the reservoir, as well as the manner in which it may beformed, are as described above. The composition and structure of thebarrier layer, as well as the manner in which it may be formed, are asdescribed above.

The barrier layer has a first permeability to the therapeutic agentprior to swelling of the swellable material and a second permeability tothe therapeutic agent after swelling of the swellable material, with thesecond permeability being greater than the first permeability. Incertain embodiments, the barrier layer may have regions of structuralweakness as described above. When the swellable material swells, itapplies outward pressure against the barrier layer. The strain imposedby this pressure causes the formation of discontinuities in the barrierlayer, which increases the permeability of the barrier layer. Thus, thesecond permeability of the barrier layer is provided by discontinuitiesthat form in the barrier layer upon swelling of the swellable material.Where the barrier layer has a plurality of regions of structuralweakness, the discontinuities may form in these regions.

In certain embodiments, the swellable material is a water-swellablepolymer that swells when it becomes hydrated. In such cases, the medicaldevice is designed such that the water-swellable polymer becomeshydrated when the medical device is exposed to an aqueous environment(e.g., body fluid or tissue). The aqueous fluid may be distributed tothe water-swellable polymer through various pathways. In certainembodiments, aqueous fluid has access to the water-swellable polymer viaa pathway that does not involve the barrier layer. For example, aqueousfluid may have access to the water-swellable polymer through anotherportion of the medical device, or aqeuous fluid may be actively suppliedto the water-swellable polymer by the medical device.

In certain embodiments, aqueous fluid from the external environmentaccesses the water-swellable polymer by passing through the barrierlayer, which is allowed by a first, initial permeability of the barrierlayer. This first, initial permeability of the barrier layer may beprovided in various ways. In some cases, the barrier layer may be porousor semi-permeable. In some cases, the barrier layer may have one or moreinitially present discontinuities that allow the penetration of aqueousfluid through the barrier layer. These initially present discontinuitiesmay be formed in various ways. One such method involves heating and/orcooling the barrier layer, which would cause thermal expansion and/orcontraction of the barrier layer and result in the formation ofdiscontinuities. For example, the barrier layer may be cooled by dippingthe medical device into a cold solvent mixture or a cryogenic liquid(e.g., liquid nitrogen). In another example, the barrier layer may besubjected to alternating cycles of heating and cooling (or vice versa).

Any of a number of various types of water-swellable polymers known inthe art may be used, including those that form hydrogels. Other examplesof water-swellable polymers include polyethylene oxide, hydroxypropylmethylcellulose, poly(hydroxyalkyl methacrylate), polyvinyl alcohol, andpolyacrylic acid. The water-swellable polymer may be applied to themedical device in various ways. For example, the water-swellable polymermay be provided in the form of gels, layers, fibers, agglomerates,blocks, granules, particles, capsules, or spheres. In some cases, thewater-swellable polymer is contained within or underneath a polymerlayer containing the therapeutic agent. In such cases, the polymer layermay serve to control the rate at which the water-swellable polymerbecomes hydrated.

The following non-limiting examples further illustrate variousembodiments of this aspect of the present invention. In one example,referring to the embodiment shown in FIGS. 7A and 7B, a stent strut 20of a stent is coated with a water-swellable layer 100 formed of ahydrogel. Water-swellable layer 100 is coated with a polymer layer 110containing a therapeutic agent. Polymer layer 110 is coated with abarrier layer 120, which has multiple small pores 122 to allow thepassage of fluids through barrier layer 120 so that water-swellablelayer 100 can become hydrated when the stent is exposed to an aqueousenvironment. In alternate embodiments, the positions of water-swellablelayer 100 and polymer layer 110 may be switched.

In operation, when the stent is delivered to a target body site, bodyfluid flows through pores 122 of barrier layer 120, diffuses throughpolymer layer 110, and hydrates the hydrogel in water-swellable layer100. As shown in FIG. 7B, hydration of the hydrogel causes volumeexpansion of water-swellable layer 100, which causes the formation ofcracks 124 in barrier layer 120. These cracks 124 allow the passage oftherapeutic agent from polymer layer 110 through barrier layer 120 tothe external environment.

In another example, referring to the embodiment shown in FIGS. 8A and8B, a stent strut 20 of a stent is coated with a polymer layer 114containing a therapeutic agent. Embedded in polymer layer 114 arecapsules 102 which contain a hydrogel. Polymer layer 114 is coated witha barrier layer 130, which is semi-permeable to allow the passage offluids through barrier layer 130.

In operation, when the stent is delivered to a target body site, bodyfluid flows through semi-permeable barrier layer 130, diffuses throughpolymer layer 114, and hydrates the hydrogel in capsules 102. As shownin FIG. 8B, hydration of the hydrogel causes the volume expansion ofcapsules 102, which in turn, causes volume expansion of polymer layer114. This volume expansion of polymer layer 114 causes the formation ofcracks 132 in barrier layer 130. These cracks 132 allow the passage oftherapeutic agent from polymer layer 114 through barrier layer 132 tothe external environment.]

In another embodiment, the swellable material is an oxidizable metalthat undergoes volume expansion upon oxidation (e.g., iron). Theoxidation can occur upon exposure to an aqueous environment. As such,the oxidizable metal may be used in a manner similar to that for thewater-swellable polymer described above.

In yet another aspect, the present invention provides a medical devicehaving a multi-layered coating. The multi-layered coating comprises afirst reservoir layer over a surface of the medical device, wherein thefirst reservoir layer comprises a first therapeutic agent. Further, afirst barrier layer is disposed over the first reservoir layer, whereinthe first barrier layer comprises a first inorganic material. Further, asecond reservoir layer is disposed over the first barrier layer, whereinthe second reservoir layer comprises a second therapeutic agent. Thereservoir layers are formed using a material that is capable ofretaining or holding the therapeutic agent, such as polymeric materials.

The first and second therapeutic agents may be the same or different.For example, one therapeutic agent may be an anti-thrombotic agent andthe other therapeutic agent may be an anti-inflammatory agent to providea combination treatment. Also, various characteristics of the first andsecond reservoir layers may be the same or different. Suchcharacteristics include, for example, their composition, their density,their thicknesses, and the rate at which the therapeutic agents diffusethrough the polymer layers. By independently controlling thecharacteristics of each reservoir layer, the release rate of thetherapeutic agents can be adjusted.

Further, a second barrier layer is disposed over the second reservoirlayer, wherein the second barrier layer comprises a second inorganicmaterial. The composition and structure of the barrier layers, as wellas the manner in which they may be formed, are as described above. Eachbarrier layer may each independently have their own variouscharacteristics, including their composition, density, thickness, andpermeability to the therapeutic agents.

Further, a plurality of excavated regions (as defined above) penetratethrough at least a partial thickness of the multi-layered coating. Theexcavated regions provide a means by which therapeutic agents in thereservoir layers may be released into the external environment.

For example, referring to the embodiment shown in FIG. 9, a stent strut20 of a stent has a multi-layered coating 170. The first layer inmulti-layered coating 170 is a first reservoir layer 140 containing afirst therapeutic agent. First reservoir layer 140 is coated with afirst barrier layer 150 which, in this particular embodiment, isimpermeable to the first therapeutic agent. First barrier layer 150 iscoated with a second reservoir layer 142 which contains a secondtherapeutic agent which, in this particular embodiment, is differentfrom the first therapeutic agent. Second reservoir layer 142 is coatedwith a second barrier layer 152 which, in this particular embodiment, isimpermeable to the second therapeutic agent. Multiple slots 160penetrating through the full thickness of multi-layered coating 170 arecreated by laser ablation. In this particular embodiment, slots 160 havea width in the range of 100 nm to 1 μm, but other widths are alsopossible depending upon the particular application. In operation, whenthe stent is delivered to a body site, the therapeutic agents diffuseout of reservoir layers 140 and 142 through the side aspects (e.g., sideaspect 146) of reservoir layers 140 and 142. The therapeutic agents arethen released out of slots 160.

The excavated regions may have various geometries and dimensions,including various sizes, widths, shapes, and degrees of penetrationthrough the multi-layered coating. This feature may be useful in varyingthe release rate of the therapeutic agents. For example, referring tothe embodiment shown in FIG. 10, a stent strut 20 of a stent has amulti-layered coating 172 with slots (162, 164, 166, and 168) havingvarious different dimensions and geometries. Multi-layered coating 172has a first reservoir layer 140 containing a first therapeutic agent, afirst barrier layer 150, a second reservoir layer 142 containing asecond therapeutic agent, and a second barrier layer 152. Slot 162penetrates partially through multi-layered coating 172 such that onlyreservoir layer 142 is exposed. Because of this geometry, only the firsttherapeutic agent in reservoir layer 142 would be released from slot162. Slot 164 also penetrates partially through the multi-layeredcoating, but both reservoir layer 140 and 142 are exposed. Slot 166 hasa slanted geometry with respect to the plane of multi-layered coating172. A slot having this geometry may be useful in enlarging the sideaspect surface (e.g., side aspect 144) of reservoir layers 140 and 142,which would increase the rate at which the therapeutic agents diffuseout of the layers. Slot 168 has a wedge-shaped geometry, which like slot166, enlarges the side aspect surface of reservoir layers 140 and 142,which would increase the rate at which the therapeutic agents diffuseout of the layers.

In certain embodiments, the excavated regions on one portion of themedical device have different characteristics than the excavated regionson another portion of the medical device. These differentcharacteristics can involve different geometries or dimensions, or adifferent arrangement (e.g., pattern, number, or density) of theexcavated regions. This feature may be useful in providing differenttherapeutic agent release rates on different portions of the medicaldevice, or the release of different therapeutic agents on differentportions of the medical device. For example, a vascular stent may havelarger or a higher density of excavated regions at the end portions ofthe stent than at the intermediate portions of the stent to reduce theunwanted “edge-effect” that sometimes occurs with stent implantation.

The first and second barrier layers may have varying degrees ofpermeability to the therapeutic agents, or be completely impermeable. Insome cases, the first barrier layer and/or second barrier layer areimpermeable so that the therapeutic agent is released only though theexcavated regions in the multi-layered coating. The permeability of thebarrier layers may be controlled in various ways, including selectingthe thickness, the density, the deposition process used, and thecomposition of the barrier layers. By individually adjusting thepermeability of the barrier layers, the release rate profiles of thetherapeutic agents may be further controlled.

In certain embodiments, the multi-layered coating comprises a pluralityof alternating reservoir layers and barrier layers. For example, theremay be a third reservoir layer disposed over the second barrier layer,wherein the third reservoir layer comprises a third therapeutic agent;and a third barrier layer disposed over the third reservoir layer,wherein the third barrier layer comprises a third inorganic material.

In yet another aspect, the present invention provides a medical devicehaving a polymer layer, which comprises a block copolymer and atherapeutic agent. Further, a barrier layer is disposed over the polymerlayer. The barrier layer comprises an inorganic material and has aplurality of discontinuities. The composition and structure of thereservoir, as well as the manner in which it may be formed, are asdescribed above. The composition and structure of the barrier layer, aswell as the manner in which it may be formed, are as described above.

The inventors have discovered that depositing a thin layer of gold (bysputter deposition) onto a film of SIBS block copolymer on a stainlesssteel coupon unexpectedly resulted in the formation of nanometer-sized(about 20 nm wide) cracks in a reticulated pattern, as shown under60,000-fold magnification in FIG. 11. It is believed that this patternof cracks in the gold layer follows the particular surface morphology ofthe SIBS polymer film. Referring to FIG. 12, an atomic force microscopyimage of the SIBS polymer film (deposited by evaporation on a stainlesssteel stent shows the surface morphology of this film as having featuressized from about 30-90 nm. These surface features are believed to becaused by microphase-separated domains of the block copolymers in thefilm.

Therefore, in this aspect of the present invention, the polymer layer(comprising a block copolymer) and the barrier layer have a synergisticrelationship because the resulting formation of discontinuities in thebarrier layer allows for the release of therapeutic agent in the polymerlayer to the external environment. Also, the polymer layer and thebarrier layer have an additional synergistic relationship because theresulting surface morphology of the barrier layer is believed to becapable of promoting endothelial cell attachment and/or growth, whichmay improve the therapeutic effectiveness of medical devices that areimplanted in blood vessels.

In certain embodiments, the surface morphology of the polymer layercomprises a plurality of microphase-separated domains. In some cases,the surface morphology of the barrier layer follows the surfacemorphology of the polymer layer. In some cases, the discontinuities inthe barrier layer follow the surface morphology of the polymer layer.Various characteristics of the microphase-separated domains (e.g., theirsize, geometry, and periodicity) on the surface of the polymer layerwill depend upon the specific characteristics of the block copolymer,such as the relative chain lengths, positions, and composition of theblocks. As such, the block copolymer can be selected to achieve thedesired surface morphology in the polymer layer, which in turn, willinfluence the formation of discontinuities and/or the surface morphologyof the barrier layer.

In certain embodiments, the surface morphology of the barrier layercomprises a plurality of features elements or feature domains having asize that promotes endothelial cell attachment and/or growth. As usedherein, the term “feature element” refers to any feature on a surfacethat causes the surface to be uneven, non-smooth, or discontinuous. Forexample, the feature elements may be bumps, nodules, ridges, grains,protrusions, pits, holes, openings, cracks, fracture lines, pores,grooves, channels, etc. As used herein, the term “feature domain” refersto a domain that is defined by one or more feature elements. Forexample, referring to schematic illustration of FIG. 13, a surface 200comprises multiple grooves 202 which define a series of pattern domains204. Grooves 202 would be considered feature elements and patterndomains 204 would be considered feature domains. The size of a featureelement or feature domain, as used herein, is intended to be measuredalong its shortest axis. In some cases, the feature elements or featuredomains have an average size of less than 200 nm. In some cases, thefeature elements or feature domains have an average size in the range of10 nm to 200 nm; and in some cases, in the range of 30 nm to 90 nm. Thepattern of the feature elements or feature domains may be regular orirregular, ordered or random, and have varying densities.

In certain embodiments, the polymer layer is exposed to a solvent whichdissolves the polymeric material in the polymer layer, but does notdissolve the therapeutic agent. In some cases, the solvent may accessthe polymer layer through the discontinuities in the barrier layer. Forexample, referring to the embodiment shown in FIG. 14A, a medical device15 is coated with a polymer layer 180 formed of a block copolymer.Polymer layer 180 contains particles 182 of a therapeutic agent. Abarrier layer 190 is deposited over polymer layer 180, and cracks 192form in barrier layer 190 due to the surface morphology of polymer layer180. Medical device 15 is then exposed to a solvent which penetratesthrough the cracks 192 of barrier layer 190 and dissolves the polymericmaterial in polymer layer 180. However, the particles 182 of thetherapeutic agent are left intact. As shown in FIG. 14B, this results ina coating in which the therapeutic agent is contained in a polymer-freelayer 184 under barrier layer 190. This feature may be useful inreducing exposure of body tissue to polymeric materials which may not befully biocompatible. In some cases, barrier layer 190 may then beaugmented by further depositing additional inorganic material (e.g., abiodegradable metal such as a magnesium alloy, iron, or zinc) ontobarrier layer 190. Augmenting barrier layer 190 may be useful inreducing the permeability of barrier layer 190, and thereby, reducingthe rate at which the therapeutic agent is released.

In an experimental example, a coating was formed by sputter-depositing alayer of gold onto an SIBS block copolymer film stainless steel couponcontaining paclitaxel particles. This coating was then exposed totoluene, which penetrated through the cracks in the gold film anddissolved the SIBS polymer. FIG. 15 shows the surface (under 134,00-foldmagnification) of the gold layer, in which the preserved paclitaxelparticles are evident as bumps (black arrow) in the layer. Additionalgold material was then sputtered-deposited onto this coating to form thecoating seen in FIG. 16, which shows the surface under 60,000-foldmagnification.

Non-limiting examples of medical devices that can be used with thepresent invention include stents, stent grafts, catheters, guide wires,neurovascular aneurysm coils, balloons, filters (e.g., vena cavafilters), vascular grafts, intraluminal paving systems, pacemakers,electrodes, leads, defibrillators, joint and bone implants, spinalimplants, access ports, intra-aortic balloon pumps, heart valves,sutures, artificial hearts, neurological stimulators, cochlear implants,retinal implants, and other devices that can be used in connection withtherapeutic coatings. Such medical devices are implanted or otherwiseused in body structures, cavities, or lumens such as the vasculature,gastrointestinal tract, abdomen, peritoneum, airways, esophagus,trachea, colon, rectum, biliary tract, urinary tract, prostate, brain,spine, lung, liver, heart, skeletal muscle, kidney, bladder, intestines,stomach, pancreas, ovary, uterus, cartilage, eye, bone, joints, and thelike.

The therapeutic agent used in the present invention may be anypharmaceutically acceptable agent such as a non-genetic therapeuticagent, a biomolecule, a small molecule, or cells.

Exemplary non-genetic therapeutic agents include anti-thrombogenicagents such heparin, heparin derivatives, prostaglandin (includingmicellar prostaglandin E1), urokinase, and PPack (dextrophenylalanineproline arginine chloromethylketone); anti-proliferative agents such asenoxaparin, angiopeptin, sirolimus (rapamycin), tacrolimus, everolimus,zotarolimus, monoclonal antibodies capable of blocking smooth musclecell proliferation, hirudin, and acetylsalicylic acid; anti-inflammatoryagents such as dexamethasone, rosiglitazone, prednisolone,corticosterone, budesonide, estrogen, estrodiol, sulfasalazine,acetylsalicylic acid, mycophenolic acid, and mesalamine;anti-neoplastic/anti-proliferative/anti-mitotic agents such aspaclitaxel, epothilone, cladribine, 5-fluorouracil, methotrexate,doxorubicin, daunorubicin, cyclosporine, cisplatin, vinblastine,vincristine, epothilones, endostatin, trapidil, halofuginone, andangiostatin; anti-cancer agents such as antisense inhibitors of c-myconcogene; anti-microbial agents such as triclosan, cephalosporins,aminoglycosides, nitrofurantoin, silver ions, compounds, or salts;biofilm synthesis inhibitors such as non-steroidal anti-inflammatoryagents and chelating agents such as ethylenediaminetetraacetic acid,O,O′-bis(2-aminoethyl)ethyleneglycol-N,N,N′,N′-tetraacetic acid andmixtures thereof, antibiotics such as gentamycin, rifampin, minocyclin,and ciprofloxacin; antibodies including chimeric antibodies and antibodyfragments; anesthetic agents such as lidocaine, bupivacaine, andropivacaine; nitric oxide; nitric oxide (NO) donors such as linsidomine,molsidomine, L-arginine, NO-carbohydrate adducts, polymeric oroligomeric NO adducts; anti-coagulants such as D-Phe-Pro-Argchloromethyl ketone, an RGD peptide-containing compound, heparin,antithrombin compounds, platelet receptor antagonists, anti-thrombinantibodies, anti-platelet receptor antibodies, enoxaparin, hirudin,warfarin sodium, Dicumarol, aspirin, prostaglandin inhibitors, plateletaggregation inhibitors such as cilostazol and tick antiplatelet factors;vascular cell growth promotors such as growth factors, transcriptionalactivators, and translational promotors; vascular cell growth inhibitorssuch as growth factor inhibitors, growth factor receptor antagonists,transcriptional repressors, translational repressors, replicationinhibitors, inhibitory antibodies, antibodies directed against growthfactors, bifunctional molecules consisting of a growth factor and acytotoxin, bifunctional molecules consisting of an antibody and acytotoxin; cholesterol-lowering agents; vasodilating agents; agentswhich interfere with endogenous vascoactive mechanisms; inhibitors ofheat shock proteins such as geldanamycin; angiotensin converting enzyme(ACE) inhibitors; beta-blockers; βAR kinase (βARK) inhibitors;phospholamban inhibitors; protein-bound particle drugs such asABRAXANE™; structural protein (e.g., collagen) cross-link breakers suchas alagebrium (ALT-711); any combinations and prodrugs of the above.

Exemplary biomolecules include peptides, polypeptides and proteins;oligonucleotides; nucleic acids such as double or single stranded DNA(including naked and cDNA), RNA, antisense nucleic acids such asantisense DNA and RNA, small interfering RNA (siRNA), and ribozymes;genes; carbohydrates; angiogenic factors including growth factors; cellcycle inhibitors; and anti-restenosis agents. Nucleic acids may beincorporated into delivery systems such as, for example, vectors(including viral vectors), plasmids or liposomes.

Non-limiting examples of proteins include serca-2 protein, monocytechemoattractant proteins (MCP-1) and bone morphogenic proteins(“BMP's”), such as, for example, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6(VGR-1), BMP-7 (OP-1), BMP-8, BMP-9, BMP-10, BMP-11, BMP-12, BMP-13,BMP-14, BMP-15. Preferred BMP's are any of BMP-2, BMP-3, BMP-4, BMP-5,BMP-6, and BMP-7. These BMPs can be provided as homodimers,heterodimers, or combinations thereof, alone or together with othermolecules. Alternatively, or in addition, molecules capable of inducingan upstream or downstream effect of a BMP can be provided. Suchmolecules include any of the “hedghog” proteins, or the DNA's encodingthem. Non-limiting examples of genes include survival genes that protectagainst cell death, such as anti-apoptotic Bcl-2 family factors and Aktkinase; serca 2 gene; and combinations thereof. Non-limiting examples ofangiogenic factors include acidic and basic fibroblast growth factors,vascular endothelial growth factor, epidermal growth factor,transforming growth factors α and β, platelet-derived endothelial growthfactor, platelet-derived growth factor, tumor necrosis factor α,hepatocyte growth factor, and insulin-like growth factor. A non-limitingexample of a cell cycle inhibitor is a cathespin D (CD) inhibitor.Non-limiting examples of anti-restenosis agents include p15, p16, p18,p19, p21, p27, p53, p57, Rb, nFkB and E2F decoys, thymidine kinase andcombinations thereof and other agents useful for interfering with cellproliferation.

Exemplary small molecules include hormones, nucleotides, amino acids,sugars, and lipids and compounds have a molecular weight of less than100 kD.

Exemplary cells include stem cells, progenitor cells, endothelial cells,adult cardiomyocytes, and smooth muscle cells. Cells can be of humanorigin (autologous or allogenic) or from an animal source (xenogenic),or genetically engineered. Non-limiting examples of cells include sidepopulation (SP) cells, lineage negative (Lin⁻) cells includingLin-CD34⁻, Lin⁻CD34⁺, Lin⁻cKit⁺, mesenchymal stem cells includingmesenchymal stem cells with 5-aza, cord blood cells, cardiac or othertissue derived stem cells, whole bone marrow, bone marrow mononuclearcells, endothelial progenitor cells, skeletal myoblasts or satellitecells, muscle derived cells, go cells, endothelial cells, adultcardiomyocytes, fibroblasts, smooth muscle cells, adult cardiacfibroblasts+5-aza, genetically modified cells, tissue engineered grafts,MyoD scar fibroblasts, pacing cells, embryonic stem cell clones,embryonic stem cells, fetal or neonatal cells, immunologically maskedcells, and teratoma derived cells. Any of the therapeutic agents may becombined to the extent such combination is biologically compatible.

The polymeric materials used in the present invention may comprisepolymers that are biodegradable or non-biodegradable. Non-limitingexamples of suitable non-biodegradable polymers include polystyrene;polystyrene maleic anhydride; block copolymers such asstyrene-isobutylene-styrene block copolymers (SIBS) andstyrene-ethylene/butylene-styrene (SEBS) block copolymers;polyvinylpyrrolidone including cross-linked polyvinylpyrrolidone;polyvinyl alcohols, copolymers of vinyl monomers such as EVA; polyvinylethers; polyvinyl aromatics; polyethylene oxides; polyesters includingpolyethylene terephthalate; polyamides; polyacrylamides includingpoly(methylmethacrylate-butylacetate-methylmethacrylate) blockcopolymers; polyethers including polyether sulfone; polyalkylenesincluding polypropylene, polyethylene and high molecular weightpolyethylene; polyurethanes; polycarbonates, silicones; siloxanepolymers; cellulosic polymers such as cellulose acetate; polymerdispersions such as polyurethane dispersions (BAYHYDROL®); squaleneemulsions; and mixtures and copolymers of any of the foregoing.

Non-limiting examples of suitable biodegradable polymers includepolycarboxylic acid, polyanhydrides including maleic anhydride polymers;polyorthoesters; poly-amino acids; polyethylene oxide; polyphosphazenes;polylactic acid, polyglycolic acid and copolymers and mixtures thereofsuch as poly(L-lactic acid) (PLLA), poly(D,L-lactide), poly(lacticacid-co-glycolic acid), 50/50 (DL-lactide-co-glycolide); polydioxanone;polypropylene fumarate; polydepsipeptides; polycaprolactone andco-polymers and mixtures thereof such aspoly(D,L-lactide-co-caprolactone) and polycaprolactone co-butylacrylate; polyhydroxybutyrate valerate and blends; polycarbonates suchas tyrosine-derived polycarbonates and acrylates, polyiminocarbonates,and polydimethyltrimethylcarbonates; cyanoacrylate; calcium phosphates;polyglycosaminoglycans; macromolecules such as polysaccharides(including hyaluronic acid; cellulose, and hydroxypropyl methylcellulose; gelatin; starches; dextrans; alginates and derivativesthereof), proteins and polypeptides; and mixtures and copolymers of anyof the foregoing. The biodegradable polymer may also be a surfaceerodable polymer such as polyhydroxybutyrate and its copolymers,polycaprolactone, polyanhydrides (both crystalline and amorphous),maleic anhydride copolymers, and zinc calcium phosphate.

The foregoing description and examples have been set forth merely toillustrate the invention and are not intended to be limiting. Each ofthe disclosed aspects and embodiments of the present invention may beconsidered individually or in combination with other aspects,embodiments, and variations of the invention. Modifications of thedisclosed embodiments incorporating the spirit and substance of theinvention may occur to persons skilled in the art and such modificationsare within the scope of the present invention.

1. A medical device having a first configuration and a secondconfiguration, wherein the medical device comprises: a reservoircontaining a therapeutic agent; and a barrier layer disposed over thereservoir, wherein the barrier layer comprises an inorganic material;wherein the barrier layer has a first permeability to the therapeuticagent when the medical device is in the first configuration and a secondpermeability to the therapeutic agent when the medical device is in thesecond configuration, and wherein the second permeability is greaterthan the first permeability.
 2. The medical device of claim 1, whereinthe medical device is an expandable medical device, and wherein thefirst configuration is an unexpanded configuration and the secondconfiguration is an expanded configuration.
 3. The medical device ofclaim 2, wherein the barrier layer has a plurality of regions ofstructural weakness.
 4. The medical device of claim 3, wherein theregions of structural weakness are regions where the barrier layer hasreduced thickness.
 5. The medical device of claim 3, wherein the regionsof structural weakness form a pre-determined fracture pattern for thebarrier layer.
 6. The medical device of claim 3, wherein discontinuitiesare formed in the regions of structural weakness when the configurationof the medical device changes from the unexpanded configuration to theexpanded configuration.
 7. The medical device of claim 4, wherein theregions of reduced thickness are excavated regions in which material hasbeen removed from the barrier layer.
 8. The medical device of claim 7,wherein the excavated regions contain a biodegradable filler material.9. The medical device of claim 8, wherein the filler material isreleased from the excavated regions when the configuration of themedical device changes from the unexpanded configuration to the expandedconfiguration in an aqueous environment.
 10. The medical device of claim4, wherein the barrier layer is disposed on a textured surface, andwherein the regions of reduced thickness are located over the protrudingfeatures of the textured surface.
 11. The medical device of claim 4,wherein the barrier layer is formed by a layer deposition process, andwherein the regions of reduced thickness are formed during the layerdeposition process.
 12. The medical device of claim 3, wherein theregions of structural weakness in a first portion of the medical devicehave a different characteristic than the regions of structural weaknessin a second portion of the medical device.
 13. The medical device ofclaim 12, wherein the second portion has a greater density of regions ofstructural weakness than the first portion.
 14. The medical device ofclaim 12, wherein the regions of structural weakness are regions wherethe barrier layer has reduced thickness, and wherein the regions ofreduced thickness are thinner in the second portion than in the firstportion.
 15. The medical device of claim 1, wherein the reservoircontaining the therapeutic agent is a polymer layer.
 16. The medicaldevice of claim 1, wherein the inorganic material is a metal or metaloxide.
 17. The medical device of claim 1, wherein the first permeabilityis negligible or zero.
 18. The medical device of claim 1, wherein thefirst permeability does not provide a therapeutically effective releaseprofile of the therapeutic agent, and wherein the second permeabilityprovides a therapeutically effective release profile of the therapeuticagent.
 19. A method of forming a coating on a medical device,comprising: providing a medical device; disposing a therapeutic agentover a surface of the medical device; disposing a barrier layer over thetherapeutic agent, wherein the barrier layer comprises an inorganicmaterial; and removing portions of the barrier layer to form regions ofstructural weakness in the barrier layer.
 20. The method of claim 19,wherein the step of removing is performed using an energetic beam. 21.The method of claim 20, wherein the step of removing is performed bylaser ablation.
 22. The method of claim 19, wherein the step ofdisposing the barrier layer comprises depositing the inorganic materialover the therapeutic agent by a layer deposition process.
 23. The methodof claim 22, wherein the layer deposition process is a nanoparticledeposition process.
 24. The method of claim 19, wherein more material isremoved from the barrier layer at a first portion of the medical devicethan at a second portion of the medical device.
 25. A medical devicecomprising: a reservoir containing a therapeutic agent; a barrier layerdisposed over the reservoir, wherein the barrier layer comprises aninorganic material; and a swellable material disposed between thebarrier layer and a surface of the medical device, wherein the swellablematerial is a material that swells upon exposure to an aqueousenvironment.
 26. The medical device of claim 25, wherein the barrierlayer has a first permeability to the therapeutic agent prior toswelling of the swellable material and a second permeability to thetherapeutic agent after swelling of the swellable material, and whereinthe second permeability is greater than the first permeability.
 27. Themedical device of claim 26, wherein the first permeability is providedby one or more discontinuities in the barrier layer.
 28. The medicaldevice of claim 27, wherein the swelling of the swellable materialcauses the formation of further discontinuities in the barrier layer.29. The medical device of claim 25, wherein the medical device furthercomprises an intermediate layer disposed between the medical device andthe barrier layer, wherein the intermediate layer comprises a polymericmaterial.
 30. The medical device of claim 29, wherein the intermediatelayer contains the reservoir containing the therapeutic agent.
 31. Themedical device of claim 30, wherein the medical device further comprisesa swellable layer disposed between the medical device and the barrierlayer, and wherein the swellable layer contains the swellable material.32. The medical device of claim 30, wherein the intermediate layerfurther comprises the swellable material.
 33. The medical device ofclaim 32, wherein the swellable material is contained in capsules. 34.The medical device of claim 25, wherein the barrier layer has aplurality of regions of structural weakness.
 35. The medical device ofclaim 25, wherein the swellable material is a water-swellable polymer.36. The medical device of claim 25, wherein the swellable material is anoxidizable metal that swells upon oxidation.
 37. The medical device ofclaim 27, wherein the one or more discontinuities are created by coolingthe barrier layer.
 38. The medical device of claim 37, wherein thebarrier layer is cooled by exposure to a cryogenic liquid.
 39. Themedical device of claim 27, wherein the one or more discontinuities arecreated by at least one cycle of heating and then cooling the barrierlayer, or at least one cycle of cooling and then heating the barrierlayer.
 40. A medical device having a multi-layered coating, wherein themulti-layered coating comprises: a first reservoir layer over a surfaceof the medical device, wherein the first reservoir layer comprises afirst therapeutic agent; a first barrier layer over the first reservoirlayer, wherein the first barrier layer comprises a first inorganicmaterial; a second reservoir layer over the first barrier layer, whereinthe second reservoir layer comprises a second therapeutic agent; asecond barrier layer over the second reservoir layer, wherein the secondbarrier layer comprises a second inorganic material; and a plurality ofexcavated regions penetrating through at least a partial thickness ofthe multi-layered coating.
 41. The medical device of claim 40, whereinat least one of the plurality of excavated regions penetrates throughthe full thickness of the multi-layered coating.
 42. The medical deviceof claim 40, wherein at least one of the plurality of excavated regionspenetrates through only a partial thickness of the multi-layeredcoating.
 43. The medical device of claim 40, wherein at least one of theplurality of excavated regions has a slanted geometry with respect tothe plane of the multi-layered coating.
 44. The medical device of claim40, wherein the first therapeutic agent is different from the secondtherapeutic agent.
 45. The medical device of claim 40, wherein the firstreservoir layer or the second reservoir layer is formed of a polymericmaterial.
 46. The medical device of claim 40, wherein the thickness ofthe first reservoir layer is different from the thickness of the secondreservoir layer.
 47. The medical device of claim 40, further comprisinga third reservoir layer disposed over the second barrier layer, whereinthe third reservoir layer comprises a third therapeutic agent, and athird barrier layer disposed over the third reservoir layer, wherein thethird barrier layer comprises a third inorganic material.
 48. Themedical device of claim 47, wherein the multi-layered coating comprisesa plurality of alternating reservoir layers and barrier layers.
 49. Themedical device of claim 40, wherein at least one characteristic of theexcavated regions on one portion of the medical device is different fromthat of the excavated regions on another portion of the medical device.50. The medical device of claim 49, wherein the size of the excavatedregions on one portion of the medical device is different from the sizeof the excavated regions on another portion of the medical device. 51.The medical device of claim 49, wherein the geometry of the excavatedregions on one portion of the medical device is different from thegeometry of the excavated regions on another portion of the medicaldevice.
 52. The medical device of claim 40, wherein the excavatedregions are created using an energetic beam.
 53. A medical devicecomprising: a polymer layer comprising a block co-polymer, wherein thepolymer layer contains a therapeutic agent; and a barrier layer disposedover the polymer layer, wherein the barrier layer comprises an inorganicmaterial, and wherein the barrier layer has a plurality ofdiscontinuities.
 54. The medical device of claim 53, wherein the polymerlayer has a surface morphology comprising a plurality ofmicrophase-separated domain structures.
 55. The medical device of claim54, wherein the discontinuities in the barrier layer follow the surfacemorphology of the polymer layer.
 56. The medical device of claim 54,wherein the surface morphology of the barrier layer follows the surfacemorphology of the polymer layer.
 57. The medical device of claim 53,wherein the surface morphology of the barrier layer is adapted topromote endothelial cell attachment and/or growth.
 58. The medicaldevice of claim 53, wherein the surface morphology of the barrier layercomprises a plurality of feature elements or feature domains thatpromote endothelial cell attachment and/or growth.
 59. The medicaldevice of claim 58, wherein the feature elements or feature domains havean average size of less than 200 nm.
 60. The medical device of claim 59,wherein the feature elements or feature domains have an average size inthe range of 30 nm to 90 nm.
 61. A method of forming a coating in amedical device, comprising: providing a medical device; disposing apolymer layer over a surface of the medical device, wherein the polymerlayer comprises a polymeric material and a therapeutic agent, whereinthe polymeric material comprises a block copolymer, and wherein thepolymer layer has a surface morphology comprising a plurality ofmicrophase-separated domain structures; and disposing a barrier layerover the polymer layer, wherein the barrier layer comprises an inorganicmaterial, and wherein the barrier layer has a plurality ofdiscontinuities that follow the surface morphology of the polymer layer.62. The method of claim 61, further comprising removing the polymericmaterial from the polymer layer.
 63. The method of claim 62, wherein thestep of removing the polymeric material comprises exposing the polymerlayer to a solvent.
 64. The method of claim 62, further comprisingdepositing additional inorganic material over the barrier layer afterthe step of removing the polymeric material.
 65. The method of claim 61,wherein the step of disposing a barrier layer comprises depositing theinorganic material over the polymer layer.
 66. The medical device ofclaim 2, wherein the medical device is a balloon.
 67. The medical deviceof claim 2, wherein the medical device is a stent.
 68. The method ofclaim 19, wherein the medical device is a balloon.
 69. The method ofclaim 19, wherein the medical device is a stent.
 70. The medical deviceof claim 25, wherein the medical device is a balloon.
 71. The medicaldevice of claim 25, wherein the medical device is a stent.
 72. Themedical device of claim 40, wherein the medical device is a balloon. 73.The medical device of claim 40, wherein the medical device is a stent.74. The medical device of claim 53, wherein the medical device is aballoon.
 75. The medical device of claim 53, wherein the medical deviceis a stent.
 76. The medical device of claim 60, wherein the medicaldevice is a balloon.
 77. The medical device of claim 60, wherein themedical device is a stent.